Substituted pyridines



United States Patent 3,413,298 SUBSTITUTED PYRIDINES John H. Biel and Edward J. Warawa, Milwaukee, Wis., as-

signors to Aldrich Chemical Company, Inc., Milwaukee, Wis., a corporation of Wisconsin No Drawing. Filed Sept. 15, 1964, Ser. No. 396,734

- Claims. (Cl. 260-295) ABSTRACT OF THE DISCLOSURE Substituted pyridines having hypocholesteremic activity are useful for lowering blood cholesterol levels.

I cholesterol level.

These and other objects which may appear as the specification proceeds are achieved by this invention which comprises the provision of compounds selected from the group consisting of compounds having the following formula O-G-R I Y- Q 34 and the pharmaceutically acceptable nontoxic salts thereof. In Formula I,

R is (lower)alkyl;

R R R and R each represent a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fiuoro, trifluoromethyl, (lower)alkyl, (lower)alkoxy, (lower)alkylthio, di(lower) alkylamino, di(lower)alkylsulfamyl, methylenedioxy, (lower)alkanoyl, phenyl, phenoxy, benzyl and cycloalkyl radicals having from 5 to 7 carbon atoms inclusive, e.g. cyclopentyl, cyclohexyl and cycloheptyl.

The pharmaceutically acceptable nontoxic salts include the organic and inorganic acid addition salts, e.-g., those prepared from acids such as hydrochloric, sulfuric, sulfamic, tartaric, fumaric, hydrobromic, hydriodic, glycolic, citric, maleic, phosphoric, succinic, acetic, nitric and the like.

The term (lower)alkyl as used herein means both straight and branched chain alkyl radicals containing from 1 to 8 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-buty'l, amyl, hexyl, Z-ethylhexyl, etc.

Similarly, where the term (lower) is used as part of the description of another group, e.g., (lower)al'koxy, it refers to the alkyl portion of such group which is therefore as described in connection with (lower)alkyl.

Preferred compounds of the present invention are those having the following formula wherein R, R R R and R are as described above.

More preferred compounds of the present invention are those having the following formula (III) ICH wherein R R R and R are as represented above.

Still more preferred compounds of the present invention are those having the following formula The compounds of this invention are valuable pharmaceutical agents. They produce a reduction in the serum cholesterol level which makes the compounds useful as hypocholesteremic agents. Thus, the compounds can be used for the treatment of hypercholesteremia.

The compounds of the present invention are produced in the following manner. The compounds of Formula I are prepared from tertiary alcohols having the following formula OH R ('J-CHG \N I R4 wherein R R R and R are as represented above. These intermediates are prepared by the reaction of a benzyl pyridyl ketone of the formula wherein R and R are as represented above, with a Grignard reagent, i.e., an aryl magnesium halide of the formula (VII) Rl wherein Hal is chloro, bromo or iodo, and R and R are 3 as represented above, or an organo-litliium compound of the formula (VIII) R wherein R and R are as represented above. The reaction is carried out in the presence of an inert solvent, e.g., tetrahydrofuran, at reflux temperature. Such procedures are described in the following references: Chem. Abstr. 57: 8540/1, 8541a; J. Am. Chem. Soc., 79: 472 (1957); I. Am. Chem. Soc., 76: 2431 (1954); and J. Med. Chem., 7: 113 (1964). The pyridyl benzyl ketones may be prepared by reacting a pyridyl carboxylic acid ester with a phenylacetonitrile, followed by hydrolysis of the nitrile to the acid and decarboxylation of the keto acid. Such a procedure is described in Chem. Abstr. 57: 854011.

Some of the pyridyl benzyl ketones which may be formed in this manner are Z-pyridyl p-chlorobenzyl ketone,

3-pyridyl m-bromobenzyl ketone,

2-pyridyl p-methoxybenzyl ketone,

2-pyridyl m,p-methylenedioxybenzyl ketone, 2-pyridyl m,p-dichlorobenzy1 ketone, 2-pyridyl m-methoxy-p-chlorobenzyl ketone, 4-pyridyl m-methoxy-p-chlorobenzyl ketone, 3-pyridyl m-trifluoromethyl-p-phenylbenzyl ketone, 4-pyridyl m-trifluoromethylbenzyl ketone and Z-pyridyl benzyl ketone.

Representative of the tertiary alcohol intermediates which may be produced in the foregoing manner are 1-(2-pyridyl)-1,2-diphenylethanol,

1-(3-pyridyl)-1,2-diphenylethanol,

1-(4-pyridyl)-1,2-diphenylethanol,

1-(2-pyridyl)-1-(m-trifiuoromethylphenyl) -2-phenylethanol,

1- (3-pyridyl )-1- (m-trifluoromethylphenyl)-2-p-chlorophenylethanol,

1-(4-pyridyl) -1-(m-trifluoromethylphenyl) -2-phenylethanol,

1-(4-pyridyl) -1-(m-trifluoromethylphenyl)-3 -pchlorophenylethanol,

1-(2-pyridyl )-1-p-tolyl-2'p-chlorophenylethanol,

1-(4-pyridyl )-1-p-chlorophenyl-2-p-tolylethano],

1-( 2-pyridyl -1-(m-trifiuoromethylphenyl) -2-pchlorophenylethanol,

1- (2-pyridyl) -1-m-chlorophenyl-Z-p-methoxyphenylethanol,

1-(4-pyridyl) -1-m4:hlorophenyl-2-p-methoxyphenylethanol,

1- (2-pyridyl -1-p-chlorophenyl-Z-p-bromophenylethanol,

1-(2-pyridyl -1,2-bis-(p-chlorophenyl ethanol, and

1-(4-pyridyl -1 ,Z-bis-(p-chlorophenyl ethanol.

The esters of this invention having the following formula wherein R, R R R and R are as represented above, are prepared by reacting an alkali metal hydride, e.g. potassium hydride, sodium hydride, with the tertiary alcohols of Formula V at reflux temperature in the presv 4 ence of an inert solvent such as tetrahydrofuran, according to the following reaction on R3 o-onrg KH N I (XII) (IF-A R3 it i 34 wherein R R R and R are as presented above, and A represents an alkali metal cation. The alkali metal salt thus produced is then reacted with the appropriate acid anhydride or acid halide to form the desired ester according to the following reaction (XIII) a i. r -Q R (XV) i O-C-R R g I t wherein R, R R R and R are as represented above, X is chloro, bromo or i OCR and R is (lower)alkyl. The reaction is carried out at reflux temperature in the presence of an inert solvent such as tetrahydrofuran. In the above procedure, if desirable, potassium hydride may be replaced by potassium amide or potassium t-butoxide.

Representative of the esters of this invention which may be produced in the foregoing manner are 1-(2-pyridyl) -1,2-diphenylethyl acetate,

1-(2-pyridyl)-1,2-diphenylethy1 propionate,

1-(2-pyridyl )-1,2-diphenylethyl pivalate,

1- 3 -pyridyl) -1,2-diphenylethyl acetate,

1-(3-pyridyl) -1,2-diphenylethyl propionate,

1-(3-pyridy1)-1,2-diphenylethy1 pivalate,

1-(4-pyridyl) -1,2-diphenylethyl acetate,

1-(4-pyridyl) -1,2-diphenylethyl propionate,

1-(4-pyridyl)-1,2-diphenylethyl pivalate,

1- (2-pyridyl) -1,2-bis-(p-chlorophenyl ethyl acetate,

1- Z-pyridyl v 1 ,2-bisp-chlorophenyl ethyl propionate,

1-( 2spyridyl) -1,2-bis- (p-chlorophenyl) ethyl pivalate,

l -(4-pyridyl -1,2-bis-(p-chlorophenyl) ethyl acetate,

1-(4-pyridyl) -1,2-bis-(p-chlorophenyl ethyl propionate,

1- (4-pyridyl -1 ,2-bisp-chlorophenyl ethyl pivalate,

l- Z-pyridyl l m-trifluoromethylphenyl -2-p-chlor0- phenylethyl acetate,

1-(2-pyridyl) -1-(m-trifiuoromethylphenyl) -2-p-chlorophenylethyl propionate,

1-(2-pyridyl) -1-(m-trifluoromethylphenyl) -2-p-chlorophenylethyl pivalate,

1-(4-pyridyl) -1-(m-trifluoromethylphenyl) -2-p-chlorophenylethyl acetate,

1- (4-pyridyl) -1-(m-trifluoromethylphenyl) -2-p-chlorophenylethyl propionate,

1- (4-pyridy1) -1- (m-trifluoromethylphenyl) -2-p-chlorophenylethyl pivalate,

1- (2-pyridyl) 1- (m-trifluoromethylphenyl) -2-p-methoxyphenylethyl acetate,

1- (2-pyridyl) -1- (m-trifluoro'methylphenyl) -2-p-methoxyphenylethyl propionate and 1- (Z-pyridyl -1-(m-trifluoromethylphenyl -2-p-methoxyphenylethyl pivalate.

The starting materials used in the processes described herein are compounds which are either commercially available, well-known in the art, or easily prepared in accordance with standard organic procedures previously described in the chemical literature.

The compounds of this invention may be administered as the free bases or in the form of their nontoxic addition salts. They may be compounded and formulated into pharmaceutical preparations in unit dosage form for oral or parenteral administration with organic or inorganic Example 1.Preparation of 1-(2-pyridyl)-1,2-

diphenylethanol OH N i Q Phenyl magnesium bromide was prepared by adding gm. of magnesium and 63 gm. of bromobenzene to tetrahydrofuran. To the cooled Grignard solution was added 76 gm. (0.38 mol) of 2-pyridyl benzyl ketone, and the solution was refluxed overnight. After cooling, 100 ml. of ice water was added, the supernatant liquid was decanted, and the residue was filtered through Celite (diatomaceous earth). The filtered material was then stirred with more tetrahydrofuran and filtered (3 times). Tetrahydrofuran was removed from the combined extract in vacuo, and the residue was extracted with methylene chloride, dried, and filtered. Removal of solvent left a residue which was crystallized from hot heptane. (Carboxymethyl)trimethylammonium chloride hydrochloride was treated with 23 gm. (0.15 mol) of Girards Reagent T. in 230 ml. ethanol and 23 ml. acetic acid. After refiuxing for 2 hours, the solution was cooled, made alkaline with sodium hydroxide solution, and extracted with methylene chloride, dried, and filtered. Removal of the solvent left 48.4 gm. of the product, 1-(2-pyridyl)l,2- diphenylethanol. The product was found not to contain the carbonyl group by infrared analysis.

The product was converted to the hydrochloride salt with gaseous hydrogen chloride in ethanol. The hydrochloride salt of 1-(2-pyridyl)-1,2-diphenylethanol, after recrystallization from acetone-ethanol, had a melting point of 198202 C., and the following elemental analysis.

ell

6 Analysis.-Calcd for C H NOCI: C, 73.27; H, 5.83; N, 4.50; C1, 11.38. Found: C, 73.04; H, 5.94; N, 4.51; Cl, 11.09.

Example 2.-Preparation of 1-(2-pyridyl)-l- (3-trifiuoromethylphenyl -2-phenylethanol r e N I 3-trifiuoromethylpheny1 magnesium bromide was prepared by adding 7.9 gm. of magnesium and 709 gm. of 3- trifluoromethylbromo-benzene to ether. 2-pyridyl benzene ketone (59.1 gm.) was then added dropwise and refluxed overnight. After cooling, ml. of ice water was added, the supernatant liquid was decanted, and the residue was filtered through Celite (diatomaceous earth). The filtered material was then stirred with more ether, and filtered (3 times). The combined ether extract was dried in vacuo, and the residue was extracted with methylene chloride, dried, and filtered. Removal of solvent left a residue which was crystallized from hot heptane. The solid was treated with 23 gm. (0.15 mol) of Girards Reagent T. in 230 ml. ethanol and 23 ml. acetic acid. After refluxing for 2 hours, the solution was cooled, made alkaline with sodium hydroxide solution, and extracted with methylene chloride, dried, and filtered. Removal of solvent left 75.4 gm. of the product, 1 (2-pyridyl)-1-(3-trifiuoromethylphenyl) 2-phenylethanol. The product was found not to contain the carbonyl group by infrared analysis.

The product was converted to the hydrochloride salt with gaseous hydrogen chloride in ethanol. The hydrochloride salt of 1-(2-pyridyl)-1-(3-trifluoromethylphenyl)- 2-phenylethanol after recrystallization from isopropanol had a melting point of 197-200 C., and the following elemental analysis.

Analysis.Calcd for C H NOCIF C, 63.30; H, 4.52; N, 3.70; Cl, 9.35. Found: C, 63.33; H, 4.52; N, 3.75.

Example 3 When, in the procedure of Example 1, Z-pyridyl benzyl ketone is replaced by an equal molar amount of S-pyridyl benzyl ketone,

4-pyridyl benzyl ketone,

2-pyridyl-4-trifiuoromethylbenzyl ketone, 3-pyridyl-4-chlorobenzyl ketone, 2-pyridyl-2-bromobenzyl ketone, 2-pyridyl-3-iodobenzyl ketone, 2-pyridyl-2,4-dichlorobenzyl ketone, 2-pyridyl-4-fiuorobenzyl ketone, 2-pyridyl-3-trifluoromethylbenzyl ketone, 4-pyridyl-4-methylbenzyl ketone, 2-pyridyl-3-methylbenzyl ketone, 2-pyridyl-4-ethylbenzyl ketone, 3-pyridyl-2-butylbenzyl ketone, 2-pyridyl-3-methoxybenzyl ketone, Z-pyridyl-2,6-dirnethylbenzyl ketone, 2-pyridyl-4-methylthiobenzyl ketone, 3-pyridyl-4trifluoromethylbenzyl ketone, 2-pyridyl-3-cyclohexylbenzy1 ketone, 2-pyridyl-4-phenylbenzyl ketone, 3-pyridyl-4-phenoxybenzyl ketone, 2-pyridyl-4-benzylbenzyl ketone, 2-pyridyl-2-acetylbenzyl ketone, 2-pyridyl-3-dimethylsu1famylbenzyl ketone, 3-pyridyl-2,3-methylenedioxybenzyl ketone, 4-pyridyl-3-dimethylaminobenzyl ketone, 2-pyridyl-2-ethoxybenzyl ketone, 2-pyridyl-3-cyclopentylbenzyl ketone and 2-pyridy1-2-methyl-4 trifluoromethylbenzyl ketone, re-

spectively,

there are obtained,

1- (3 -pyridyl) -1,2-diphenylethanol,

1 (4-pyridyl) -1,2-diphenylethanol,

1 Z-pyridyl 1 -phenyl-2- (4-trifluoromethylphenyl) ethanol,

1-( 3-pyridyl -1-phenyl-2-(4-chlorophenyl)ethanol,

1- (Z-pyridyl) l-phenyl-Z- 2-bromophenyl ethanol,

1- (Z-pyridyl) 1-phenyl-2- 3 -iodophenyl) ethanol,

1- 2-pyridyl l-phenyl-Z- (2,4-dichlorophenyl ethanol,

1 Z-pyridyl 1-phenyl-2-(4-fiuorophenyl ethanol,

1- Z-pyridyl l-phenyl-Z- 3-trifiuoromethylphenyl) ethanol,

1- (4-pyridyl I-phenyl-Z- (4-methylphenyl ethanol,

1- (2-pyridyl 1 -phenyl-2- 3 -methylphenyl) ethanol,

1- (2-pyridyl) -1-phenyl-2- (4-ethylphenyl) ethanol,

1- 3 -pyridyl) -1-phenyl-2-(Z-butylphenyl) ethanol,

1-(2-pyridyl) -1-phenyl-2-(3-methoxyphenyl) ethanol,

1-(2-pyridyl -1-phenyl-2- (2,6-dimethylphenyl) ethanol,

1- Z-pyridyl 1-phenyl-2- (4-methylthiopheny1) ethanol,

1- 3-pyridyl) l-phenyl-2- (4-trifluoromethylphenyl) ethanol,

1-(2-pyridyl)-1-phenyl-2- (3 -methylphenyl ethanol,

1- (Z-pyridyl l-phenyl-Z- (4-phenylphenyl) ethanol,

1- 3-pyridyl l-phenyl-Z (4-phepoxyphenyl) ethanol,

1- (2-pyridyl 1-phenyl-2- (4-benzylphenyl) ethanol,

1- (2-pyridyl) -1-phenyl-2- Z-aeetylphenyl) ethanol,

1- Z-pyridyl l-phenyl-Z- 3-dimethylsulfamylphenyl) ethanol,

1- 3-pyridyl) 1-phenyl-2- (2,3-methylenedioxyphcnyl) ethanol,

1- 4-pyridyl) 1- phenyl-Z- (3 -dimethylaminophenyl) ethanol,

1- 2-pyridyl l-phenyl-Z- (2-ethoxyphenyl) ethanol,

1- (Z-pyridyl) l-phenyl-Z- 3-cyclopentylpheny1) ethanol and 1- 2-pyridyl 1-phenyl-2- 2-methyl-4-trifluoromethylphenyl)ethanol, respectively.

Example 4 When, in the procedure of Example 1, phenyl magnesium bromide is replaced by an equal molar amount of Z-trifluoromethylphenyl magnesium bromide, 4-trifluoromethylphenyl magnesium bromide, 3,4-ditrifiuoromethylphenyl magnesium bromide, 3-chlorophenyl magnesium bromide, 2-bromophenyl magnesium bromide, 4-iodophenyl magnesium bromide, 3-fiuorophenyl magnesium bromide, 3-methylphenyl magnesium bromide, Z-propylphenyl magnesium bromide, 4-ethylphenyl magnesium bromide, 3,4-methylenedioxyphenyl magnesium bromide, 3-methoxyphenyl magnesium bromide, 4-acetylphenyl magnesium bromide, 2-phenoxyphenyl magnesium bromide, 2,6-dichlorophenyl magnesium bromide, 2-methyl-4-fiuorophenyl magnesium bromide, 3-methylthiophenyl magnesium bromide, 4-dimethylaminophenyl magnesium bromide, 2-chlorophenyl magnesium bromide, 4-dimethylsulfamylphenyl magnesium bromide, 3-phenylphenyl magnesium bromide, 3-benzylphenyl magnesium bromide, 3-cyclohexylphenyl magnesium bromide, 4-cycloheptylphenyl magnesium bromide and 4-tluorophenyl magnesium bromide, respectively,

there are obtained,

l-(2-pyridyl.) -1-(Z-tritluoromethylphenyl)- 2-phenylethanol,

1-(2-pyridyl)-l-(4-trifluoromethylphenyl)- Z-phenylethanol,

l- Z-pyridyl -1- (3 ,4-ditritluoromethylphcnyl 2-phenylethanol,

tar

1- -chlorophenyl -2-pheny1ethanol, 1- Z-pyridyl bromophenyl -2-phenylethanol, l-(Z-pyridyl iodophenyl )-2-phenylethanol,

(2-pyridyl)- l-(3-fluorophenyl)-2-phenylethanol, (Z-pyridyl -l-(3-methylphenyl)-2-nhenylethanol,

1-(2-pyridyl)- 1- 2-propylphenyl)-2-phenylethanol,

1-(2-pyridyl)-1-(4 ethylphenyl)-2-phenylethanol,

l-(Z-pyridyl -1-(3,4-methylenedioxyphenyl)- Z-phenylethanol,

1-(2pyridyl )-1- 3-methoxyphenyl -2-phenylethanol,

1-(2pyridyl -l-(4-acetylphenyl)-2-phenylethanol,

I-(Z-pyridyl )-l-(Z-phenoxyphenyl)-2-phenylethanol,

1-(2-pyridyl)- i- (2,6-dichlorophenyl)-2-phenylethanol,

l- Z-pyridyl -l-(S-methylthiophenyl -2-phenylethanol,

l-(2-pyridyl)-1-(4-dimethylaminophenyl)- Z-phenylethanol,

l- Z-pyridyl )-1-(2-chlorophenyl -2-phenylethanol,

l-(Z-pyridyl)-1(4-dimethylsulfamylphenyl)- Z-phenylethanol,

l-(Z-pyridyl)-1-(3-phenylphenyl )-2-phenylethanol,

l Z-pyridyl -l- 3-benzylphenyl)-2-phenylethanol,

I-(Z-pyridyl l-(3-cyclohexylphenyl)-2-phenylethanol,

1-(2-pyridyl)-1 (4-cycloheptylphenyl)- Z-phenylethanol and 1- Z-pyridyl -1-(4-fiuorophenyl -2-phenylethanol,

respectively.

Example 5 When, in the procedure of Example 2, 2-pyridyl benzyl ketone is replace-d by an equal molar amount of 3-pyridyl benzyl ketone, 4-pyridyl benzyl ketone and Z-pyridyl-(4-trifiuoromethylbenzyl ketone, respectively,

there are obtained 1-(3-pyridyl)-1-(3-trifiuoromethylphenyl)- Z-phenylethanol,

1-(4-pyridyl -1- 3-trifluoromethylphenyl)- Z-phenylethanol and 1- Z-pyridyl 1 3-trifiuoromethylphenyl -2- (4-trifiuoromethylphenyl)ethano1, respectively.

Example 6 When, in the procedure of Example 1, 2-pyridyl henzyl ketone is replaced by an equal molar amount of 3-pyridyl benzyl ketone and phenyl magnesium bromide is replaced by an equal molar amount of Z-trifiuoromethylphenyl magnesium bromide, there is obtained 1-(3-pyridyl)-1-(2 triilu oromethylphenyl -2-phenylethanol.

Example 7 When, in the procedure of Example 1, 2-pyridyl benzyl ketone is replaced by an equal molar amount of 4-pyridyl benzyl ketone and phenyl magnesium bromide is replaced by an equal molar amount of 2-trifiuoromethylphenyl magnesium bromide, there is obtained 1-(4-pyridyl)-1-(2- trifluoromethylphenyl)2-phenylethanol.

Example 8 When, in the procedure of Example 1, Z-pyridyl benzyl ketone is replaced by an equal molar amount of 3-pyridyl benzyl ketone and phenyl magnesium bromide is replaced by an equal molar amount of 4-trifiuoromethylp-henyl magnesium bromide, there is obtained 1-(3-pyridyl)-l-(4- trifiuoromethylphenyl -2-p-henylethanol.

Example 9 When, in the procedure of Example 1, Z-pyridyl benzyl ketone is replaced, by an equal molar amount of 4-pyridyl benzyl ketone and phenyl magnesium bromide is replaced by an equal molar amoun tof 4-trifiuoromethy[phenyl 9 magnesium bromide, there is obtained 1-(4-pyridyl)-1- (4-trifluoromethylphenyl)-2-phenylethanol.

Example 10.Preparation of 1,2-diphenyl-. 1-(2-pyridyl)ethyl propionate L. l -Q 1,2-diphenyl-1-(2-pyridyl)ethanol (4.5 gm., 0.016 mol) was added dropwise to 0.84 gm. of sodium hydride (51% in refluxing tetrahydrofuran. When evolution of hydrogen ceased, the solution was cooled, 2.2 gm. of propionic anhydride was added and the solution was refluxed for 0.25 hour. After concentration and ether extraction, a solid was obtained which was chromatographed on basic alumina with benzene. The eluted material was triturated with acetone to yield 2.8 gm. of solid, 1,2-diphenyl-1-(2- pyridyl)ethyl propionate, having a melting point of 154- 156 C., and the following elemental analysis.

AnaIysis.Calcd for C H NO C, 79.94; H, 6.39; N, 4.23. Found: C, 79.51; H, 6.41; N, 4.16.

Example 1l.--Preparation of 1-(2-pyridyl)-1-(3- trifluorornethylphenyl)-2-phenylethyl propionate I O-b-CHzCHa This residue was converted to a hydrochloride with dilute acid, and extracted with petroleum ether to remove mineral oil. The free base was regenerated with sodium hydroxide and extracted with chloroform. Removal of solvent left an oil which was triturated with petroleum ether.

The petroleumether soluble material crystallized to yield.

3.1 gm. of 1-(2-pyridyl)-1-(3-trifluoromethylphenyl)-2- phenylethyl propionate, having a melting point of 92-94 C., and the following elemental analysis.

AnaIysis.Calcd for C H NO F C, 69.14; H, 5.05; N, 3.50. Found: C, 69.66; H, 5.53; N, 3.45.

Example 12.-Preparation of 1-(2-pyridyl)-1,2- diphenylethyl acetate I-(Z-pyridyl)-l,2-diphenylethanl gm., 0.055 mol) was added dropwise to a suspension of 2.4-gm. of potassium hydride in refluxing tetrahydrofuran. When evolution ceased, 6.2 gm. of acetic anhydride was added, followed by refluxing overnight. Upon cooling, the solution was filtered through Celite (diatomaceous earth), 25 ml. of water was added, and the solvent was removed in vacuo. The residue was extracted with methylene chloride and dried with sodium sulfate. Removal of solvent yielded 16 gm. of a solid, 1 -(2-pyridyl)-1,2-diphenylethyl acetate,

having a melting point of 125-132 C., and having an infrared absorption spectrum as follows:

no OH absorption bands.

Example 13.Preparati0n of 1-(2-py=ridyl)-1-(3-trifluoromethylphenyl)-2-phenyl ethyl propionate 1 (2 pyridyl)-1-(3-trifluoromethylphenyl)-2-phenylethanol (25.7 gm., 0.081 mol) was added dropwise to a suspension of potassium hydride (3.6 gm.) in refluxing tetrahydrofuran. When the evolution of hydrogen cefised,

propionic anhydride was added dropwise, and the mixture was refluxed overnight. After cooling the solution and filtering through Celite (diatomaceous earth), 25 ml. of water was added, followed by removal of the solvent in vacuo. The residue was extracted with methylene chloride, and dried. Removal of solvent gave an oil which crystallized on standing to yield 28.7 gm. of a brown solid havin g an infrared absorption spectrum as follows:

no OH absorption. Trituration of 25.0 gm. of the crude solid gave 16.2 gm. of 1-(2-pyridyl)-1(3-trifluorometh ylphenyl)-2-phenyl ethyl propionate, having a melting point of 92 C., and an infrared spectrum as follows:

Example 14 When, in the procedure of Example 11, 1-(2-pyridyl) 1-(3-trifluoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of each of the products of Example 3, there are obtained,

max.

max.

1(2-pyridyl l-phenyl-Z- 2,6-dimethylphenyl ethyl propionate,

l-( Z-pyridyl) -l-phenyl-2-(4-methylthiophenyl ethyl propionate,

1- 3-pyridyl 1 -phenyl-2- 4-trifiuoromethylphenyl ethyl propionate,

l- Z-pyridyl l-phenyl-Z- 3-cyclohexylphenyl ethyl propionate,

1-(2-pyridyl)-lphenyl-2- (4-phenylphenyl) ethyl propionate,

1- (3 -pyridyl) l-phenyl-2,4-phenoxyphenyl ethyl propionate,

I-(Z-pyridyl) -l-phenyl-2- (4benzylphenyl ethyl propionate,

1- (Z-pyridyl) -1-phenyl-2- Z-acetylphenyl ethyl propronate,

l- 2-pyridyl l-phenyl-2- 3-dimethylsulfamylphenyl) ethyl propionate,

l- 3 -pyridyl l -phenyl-2- (2,3-methylenedroxyphenyl) ethyl propionate,

l- (4-pyridyl l -phenyl-2- 3-dimethylaminophenyl ethyl propionate,

1- Z-pyridyl) l -phenyl-2- 2-ethoxyphenyl ethyl propronate,

1- Z-pyridyl l -phenyl-2- 3cyclopentylphenyl) ethyl propionate, and

1- Z-pyridyl 1 -phenyl-2- 2-methyl-4-trifiuoromethylphenyl)ethyl propionate, respectively.

Example 15 When, in the procedure of Example 11, 1-(2-pyridyl)- l-(3-trifiuoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of each of the products of Example 4, there are obtained,

1- 2-pyridyl) 1- (Z-trifiuoromethylphenyl -2-phenylethyl propionate,

l-(2-pyridyl)-1-(4-trifiuoromethylphenyl)-2-phenylethyl propionate,

1-(2-pyridyl)-1-(3,4-ditrifiuoromethylphenyl)-2-phenylethyl propionate,

1- (2-pyridyl) 1- 3-chlorophenyl -2-phenylethyl propronate,

I-(Z-pyridyl)-1-(2-br0mophenyl)-2-phenylethyl propionate,

1-(2-pyridyl)-1-(4-iodopheny1)-2-phenylethyl propionate,

l-(2-pyridyl)-1-(3-fluorophenyl)-2-phenylethyl propionate,

1-(Z-pyridyl)-l-(3-methylphenyl)-2-phenylethyl propionate,

l-(2-pyridyl) -l-(2-propylphenyl)-2-phenylethyl propionate,

1- 2-pyridyl 1- 4-ethylphenyl -2-phenylethyl propionate,

1-(2-pyridyl)-l-(3,4-methylenedioxyphenyl)-2-phenylethyl propionate,

1- Z-pyridyl 1- 3-methoxyphenyl -2-phenylethyl propionate,

1- (Z-pyridyl -1- (4-acetylphenyl -2-phenylethyl propionate,

1- 2-pyridyl l (2-phenoxyphenyl -2-phenylethyl propionate,

l-(2-pyridyl) -l-(2,6-dichlorophenyl)-2-phenylethyl propionate,

1- 2-pyridyl) 1- 2-methyl-4-fiuorophenyl -2-phenylethyl propionate,

1-(2-pyridyl)-l-(3-methylthiophenyl)-2-phenylethyl propionate,

I-(Z-pyridyl)-1-(4-dimethylaminophenyl)-2-phenylethyl propionate,

1-(2-pyridyl)-l-(2-chlorophenyl)-2-phenylethyl propionate,

l-(2-pyridyl)-l-(4-dimethylsulfamylphenyl)-2-phenylethyl propionate,

l-(2-pyridyl)-l-(3-phcnylphenyl)-2-phenylethyl propionate,

1 z 1- 2-pyridyl 1-( 3-benzylphenyl -2-phenylethyl propionate, 1-(2-pyridyl)-l-(3-cyclohexylphenyl)-2-phenylethyl propionate, 1-( Z-pyridyl 1- 4-cycloheptylphenyl -2-phenylethyl propionate, and 1-(2'pyridyl)l-(4-fluorophenyl)-2-phenylethyl propionate, respectively.

Example 16 When, in the procedure of Example 11, l-(2-pyridyl)- l-(3-trifluoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of each of the products of Example 5, there are obtained,

1- 3 -pyridyl) 1- (3 -trifiuoromethylphenyl -2-phenylethyl propionate,

l- 4-pyridyl l 3-trifluoromethylphenyl -2-phenylethyl propionate, and

1- 2-pyridyl) 1- 3-trifluoromethylphenyl -2-( 4-trifiuoromethylphenyl) ethyl propionate, respectively.

Example 17 When, in the procedure of Example 11, l-(2-pyridyl)- l-(3-trifluoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of the product of Example 6, there is obtained l-(3-pyridyl)-1-(2-trifiuoromethylphenyl)-2-phenylethyl propionate.

Example 18 When, in the procedure of Example 11, 1-(2-pyridyl)- 1-(3-trifluoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of the product of Example 7, there is obtained 1-(4-pyridyl)-I-(Z-trifiuoromethylphenyl)-2-phenylethyl propionate.

Example 19 When, in the procedure of Example 11, l-(2-pyridyl)- 1-(3-trifluoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of the product of Example 8, there is obtained 1-(3-pyridyl)-1-(4-trifiuoromethylphenyl) -2-phenylethyl propionate.

Example 20 When, in the procedure of Example ll,l-(2 -pyridyl)- 1-(3-trifluoromethylphenyl)-2-phenylethanol is replaced by an equal molar amount of the product of Example 9, there is obtained l-(4-pyridyl)-1-(4-trifluoromethylphenyl)-2-phenylethyl propionate.

Example 21 When, in the procedure of Example 11, propionic anhydride is replaced by an equal molar amount of pivalic anhydride, butyric anhydride, hexanoic anhydride, octanoic anhydride, and valeric anhydride, respectively, there are obtained,

1- 2-pyridy1) 1- 3-trifiuoromethylphenyl) -2-phenylethyl pivalate,

1-(2-pyridy1)-1-(3-trifluoromethylphenyl)-2-phenylethyl butyrate,

1- 2-pyridyl 1- 3-tritluoromethylphenyl -2-phenylethyl hexanate,

1- (2-pyridyl 1- (3 -trifiuoromethylphenyl) -2-phenylethyl octanate, and

1- (2-pyridyl) -1-(3-trifiuoromethylphenyl) -2-phenylethyl valerate, respectively.

Thus, it is apparent from the foregoing description, that the objects of this invention have been attained. Novel compounds have been invented which have hypocholesteremic activity. In addition, a novel method of treating hypercholesteremia has been invented.

While this invention has been described and exemplified in terms of its preferred embodiment, those skilled in the art will appreciate that modifications can be made without departing from the spirit and scope of this invention.

4. The compound having the formula 1. A compound of the formula What is claimed is:

m m H 1 J h. F H C C C 0 n e N 5 w v m r m m r m H C i 4 o c The compound having the formula 5. The compound having the formula References Cited Wright et a1., Chemical Abstracts, vol. 60, par. 5449- Chemical Abstracts, vol. 57, par.

HENRY R. JILES, Primary Examiner.

A. L. ROTMAN, Assistant Examiner. 

